CEPP: Canadian Extracorporeal Life Support (ECLS) Protocol Project

Background Extracorporeal life support (ECLS) is associated with high morbidity and mortality. Complications and mortality are higher at lower-volume centres. Most Canadian ECLS institutions are low-volume centres. Protocols offer one way to share best practices among institutions to improve outcomes. Whether Canadian centres have ECLS protocols, and whether these protocols are comprehensive and homogenous across centres, is unknown. Methods Purposeful sampling with mixed methods was used. A Delphi panel defined key elements relevant to the ECLS process. Documentation used in the delivery of ECLS services was requested from programs. Institutional protocols were assessed using deductive coding to determine the presence of key elements. Results A total of 37 key elements spanning 5 domains (referral, initiation, maintenance, termination, and administration) were identified. Documentation from 13 institutions across 10 provinces was obtained. Institutions with heart or lung transplantation programs had more-complete documentation than did non-transplantation programs. Only 5 key elements were present in at least 50% of protocols (anticoagulation strategy, ventilation strategy, defined referral process, selection criteria, weaning process), and variation was seen in how institutions approached each of these elements. Conclusions The completeness of ECLS protocols varies across Canada. Programs describe variable approaches to key elements. This variability might represent a lack of evidence or consensus in these areas and creates the opportunity for collaboration among institutions to share protocols and best practice. The key-element framework provides a common language that programs can use to develop ECLS programs, initiate quality-improvement projects, and identify research agendas.

The use of extracorporeal life support (ECLS) has increased in the past 2 decades. Extracorporeal membrane oxygenation (ECMO), a common form of ECLS, is associated with high morbidity and mortality, 1 with variable survival to discharge of 60%, 43%, and 29% for veno-venous (VV)-ECMO, venoarterial (VA)-ECMO, and extracorporeal cardiopulmonary resuscitation (eCPR) cases, respectively. 2 In keeping with evidence from other areas of medicine, a low frequency of cases may contribute to poor outcomes. 3 In Canada, more than half of ECLS centres perform fewer than 10 VV-ECMO and 10 VA-ECMO cases annually. 4 Similarly, in Germany, the majority of ECLS cases are done in lower-volume centres (< 50 VA ECMO cases/year) despite higher complication rates and mortality in these centres. 5 Although limiting ECLS to centres of excellence will increase case numbers and concentrate expertise, the emergent nature of ECLS and the expansiveness of Canadian geography mean that ECLS will continue to be offered at smaller centres and will remain a high-stakes low-frequency event. Given this constraint, alternative solutions to improve ECLS outcomes are needed.
Standard ECLS protocols may help reduce variation in care between larger and smaller centres and have the potential to improve patient outcomes. In some instances, a hub-andspoke relationship exists, whereby smaller institutions may feed cases to larger centres. Harmonization of ECLS protocols could positively impact patient care consistency. Additionally, standard protocols for ECLS referral and initiation shorten the time to initiation, 6 which in turn is associated with improved survival. 7 Although direct evidence between protocol use and improved ECLS outcomes is lacking, it seems intuitive that implementing standard protocols may beneficially influence outcomes for these high-stakes low-frequency events and warrants further investigation. Notably, in other complex industries, establishing emergency operating procedures is an important component of ensuring safety and quality improvement. 8,9 A recent survey of Canadian centres offering ECLS showed that programs lacked protocols for important aspects of ECLS delivery, despite offering these services (eg, eCPR). 4 For centres with protocols, only limited data are available to guide which elements should be included and their implementation. [10][11][12] Better characterization of existing protocols and an understanding of their usage within Canadian programs could improve ECLS service delivery across the nation.
In this study, a Delphi process (further described in the Materials and Methods section) established key elements to include within ECLS protocols. The prevalence of these key elements was determined, and areas of consensus and uncertainty within existing ECLS program documentation from 13 Canadian centres were described. These results provide much-needed evidence regarding the current state of ECLS programs across Canadian centres, highlighting areas for future research and quality improvement.

Study design
The study was reviewed by the Western University Health Sciences Research Ethics Board, and the board determined that board oversight is not required. We employed mixed methods to characterize the current state of Canadian ECLS protocols. Utilizing a list of Canadian institutions deemed capable of delivering ECLS services from previous unpublished work, program leads were contacted via e-mail to request documentation related to ECLS delivery (eg, policy and procedures, order sets, protocols, etc). Document analysis required determination of important criteria to include within protocols (eg, anticoagulation protocol, ventilation protocol, etc). A Delphi panel was used to define these key elements. Documentation was analyzed for the presence of key elements, and areas of consensus and uncertainty were described.

Delphi panel methods
Given the lack of consensus outlining ideal Canadian ECLS protocol content, a Delphi panel was created to identify key elements that should be included. The RAND/University of California, Los Angeles Delphi Method used in similar studies was adapted for this project. 13,14 A 9-member panel with expertise in critical care, cardiac surgery, cardiology, emergency medicine, and internal medicine was assembled for this process. Panel members represented relevant disciplines, geographic distribution, and institution types, including lung transplantation, cardiac transplantation, and cardiac surgery programs. The process was anonymous and was delivered Results: A total of 37 key elements spanning 5 domains (referral, initiation, maintenance, termination, and administration) were identified. Documentation from 13 institutions across 10 provinces was obtained. Institutions with heart or lung transplantation programs had more-complete documentation than did non-transplantation programs. Only 5 key elements were present in at least 50% of protocols (anticoagulation strategy, ventilation strategy, defined referral process, selection criteria, weaning process), and variation was seen in how institutions approached each of these elements. Conclusions: The completeness of ECLS protocols varies across Canada. Programs describe variable approaches to key elements. This variability might represent a lack of evidence or consensus in these areas and creates the opportunity for collaboration among institutions to share protocols and best practice. The key-element framework provides a common language that programs can use to develop ECLS programs, initiate quality-improvement projects, and identify research agendas. electronically over 3 rounds. Table 1 provides characteristics of the Delphi panel. Round 1 asked panel members to identify key elements of the ECLS protocol/program manual. Panel members were provided with documentation explaining the purpose of the research project, examples of possible key elements and how they will be used in the study, and relevant literature. [10][11][12] Panelists were asked to identify any and all relevant key elements.
Round 2 of the Delphi process consisted of a survey that asked panelists to rate the importance of key elements generated in round 1. Similar key elements were combined along with descriptions. A 9-point Likert scale was used, and a key element was considered important if it obtained a median score of 7 or more. 13 Panelists were required to provide rationale for scores of 5 or lower.
Round 3 required panelists to approve the final list of key elements. Panelists were provided with a list of approved and rejected key elements with low score rationale. All members approved of the final list without the necessity of further rounds.

Protocol sampling
Contact information for program leads was available for 24 institutions from previous work. Program leads were contacted via e-mail and provided with the rationale for the project. Any documentation related to the delivery or administration of ECLS services was requested. Program leads were recontacted at regular intervals until a representative sample was obtained. A geographically diverse sample, representing ECLS-capable institutions was targeted, incorporating programs with differences in volume and programdevelopment robustness. Centres were categorized as heartlung transplantation capable, heart transplantation capable, and cardiac surgery only capable. Programs were recontacted until representation from all provinces was obtained.

Analysis
Deductive coding was used to analyze documents for the presence or absence of key elements. The key elements and their descriptions were used as a coding framework. 15 A key element was coded as present if the element was directly mentioned (eg, anticoagulation protocol), or if indirect evidence that it existed was present (eg, some documents had approval stamps, suggesting a regular internal review process). Any text that did not meet the predefined coding framework was highlighted through inductive coding, and a memo journal was maintained throughout the process.
These data were used to determine the completeness of protocols by institution type. Additionally, key elements were grouped by their prevalence across protocols. Key elements that were present in more than 50% of institutional protocols underwent further analysis. The coded data from each key element were extracted from the original protocols and organized by key element code. These data then underwent narrative description.
To ensure reliability of coding, 2 authors independently reviewed the coded protocols for accuracy. Member checking was also employed to ensure validity. 16 The results and analysis were shared with the Delphi panel prior to publication. Delphi panel members represented stakeholders familiar with ECLS programs, with intimate knowledge of their institutional protocols. This group also contained representation from the Canadian Cardiovascular Critical Care Society and the Canadian Critical Care Society.

Results
The Delphi process occurred over 4 months and yielded 37 key elements identified as important components of an ECLS protocol ( Table 2). These were broadly classified into 5 domains of the ECLS process (referral, initiation, maintenance, discontinuation, and administrative). The final list was approved by all 9 members of the panel.
There are 39 institutions in Canada capable of delivering ECLS. 4 Program documentation was obtained from 13 institutions (33%), representing all provinces, 2 of 4 lung/heart transplantation centres (50%), 5 of 11 heart transplantation centres (without lung transplantation; 45%), and 6 of 24 cardiac surgery-only centres (25%). The documents that were provided varied among centres and included practice guidelines, protocols, policies and procedures, and order sets. Two programs lacked any documentation but were in the process of developing protocols. Four programs provided documentation organized into "program manuals." Only 3 programs had documentation that included greater than 50% of the 37 key elements. Of these, one had a complete program manual in a single document that described roles and responsibilities, clinical management, relevant policies, and order sets. Two programs had a collection of clinical guidelines outlining the care process for specific ECLS phases (eg, initiation, weaning, etc). These documents provided clear roles and responsibilities of all team members, as well as the clinical rationale for appropriate management and troubleshooting during those phases. All centres that had more comprehensive documentation were either heart and/or lung transplantation capable centres (Fig. 1).
In regard to the programs with less-comprehensive documentation, variability was seen in the key elements that were addressed and in how they were addressed. Some programs had robust emergency ECLS procedures, whereas others had very detailed order sets with step-by-step nursing instructions. In contrast to comprehensive program manuals, these documents seemed more sporadic in the issues that were addressed. Documents more commonly focused on the roles of  Descriptive review of common key elements Figure 2 shows the prevalence of the 10 most common key elements. Five key elements were present in more than 50% of protocols (referral process, patient selection criteria, anticoagulation, ventilator management, and weaning protocol). Tables 3 through 9 provide detailed description of how each key element was addressed by the institutions. Programs varied in how they address anticoagulation and ventilator management. Less variability was seen in how institutions addressed the key elements of patient selection, weaning protocol, and referral process.

Referral process and patient selection
Program documents contained similar inclusion/exclusion criteria across programs (Tables 3-5). Specific inclusion/ exclusion criteria of each institution are listed in Tables 4 and  5. The referral process for ECMO is initiated through cardiac surgery at most institutions. A limited number of institutions have protocols in place for automatically notifying all team members once a potential candidate for ECMO has been identified.

Anticoagulation and ventilator management
Most programs used unfractionated heparin for routine anticoagulation (Tables 6 and 7). One program used lowmolecular-weight heparin as a subcutaneous injection for daily maintenance in select patients. Variation was seen in bolus dosing for cannulation (5000-30000 units), monitoring (activated clotting time vs partial thromboplastin time [PTT]) and targets for maintenance (activated clotting time: 160-250 s; partial thromboplastin time: 50-70.9 s). Only one program specifically addressed monitoring and management of coagulopathy.
Ventilator strategies generally focused on initial parameters rather than guidance related to a more longitudinal strategy (ie, maintenance and weaning). Most programs suggested an initial "lung protective strategy"; however, variation occurred in how this was defined (peak inspiratory pressure: 20-30 cm H 2 O; positive end expiratory pressure: 5-15 cm H 2 O; tidal volume: 3-4 vs 4-6 mL/kg; inspired fraction of oxygen 0.3-0.5). Some programs specified only that management should be left to the discretion of the treating team. No programs specifically addressed ventilation strategy for VA-ECMO.

Weaning protocol
Most programs described a strategy to safely facilitate a weaning trial and recommended daily assessment for consideration of weaning (Tables 8 and 9). Programs provided morespecific criteria for determination of successful weaning from VV-ECMO compared to VA-ECMO. For VA-ECMO, programs suggested echocardiographic assessment on very low flow (1.5 LPM). One program (institution 4) provided specific hemodynamic and echocardiographic criteria for consideration of a successful VA-ECMO wean.

Discussion
Using a Delphi process involving key stakeholders from across Canada, 37 key elements spanning 5 domains that should be included in ECLS protocols were identified. These key elements represent important areas to be addressed by an institution delivering ECLS services. The prevalences of key elements in existing ECLS protocols from 13 Canadian institutions were then assessed. Only 5 key elements were present in more than 50% of protocols. The prevalence of key elements in documentation varied across centres, with a higher prevalence found in centres with heart and/or lung transplantation programs. Given that the majority of ECLS cases are done at lower-volume centres in Canada, 4 and lowervolume centres have been shown to have worse outcomes, 5 this study identified potential areas for quality-improvement initiatives aimed at increasing protocol completeness and harmonization across institutions. The identification of domains and key elements of ECLS provides a workable framework for program development and quality-improvement initiatives. Although programs may use the key-element framework to develop local protocols, this study could be taken as an opportunity to begin collaborating on a national ECLS program manual and outcome sharing. This collaboration should promote information sharing across programs and reduce the burden on individual institutions as program development evolves.
Many important areas of the ECLS process remained unaddressed by the majority of institutions. Key elements in the initiation and program administrative domains were underrepresented. Program administration, including a defined process for program review, quality improvement, and team education are essential tenets of the ELSO Centre of Excellence Criteria. 17 Key elements dealing with urgent and emergent aspects of ECLS delivery (ie, initiation, emergency troubleshooting, etc.) should be protocolized. Predictable emergencies should not be dealt with on an ad hoc basis. A common practice in other industries is to develop protocols for predictable high-stakes events. 8,9 Although key elements in these areas were underrepresented, some programs did have robust protocols that could be adapted to other institutions. National collaboration on program development using the key-element framework would allow centres to share best practices and learn from other institutions.  We found that heart and/or lung transplantation centres had more complete protocols. Given that transplantation centres also have a higher volume of ECLS cases, compared with nontransplantation centres, protocol completeness likely reflects the need for a clearly defined structure and organization with respect to roles and responsibilities of ECLS stakeholders at each centre. Lower-volume centres may rely on a more ad hoc approach to delivery of ECLS services when cases arise. Although direct evidence linking protocol completeness and better ECLS outcomes at higher volume centres is lacking, national collaboration and sharing of best practices among institutions may be one avenue to ensure that similar highquality care is delivered at all Canadian institutions.
The narrative review of the 5 common key elements provides readers with a summary of how institutions approached these components of ECLS delivery. Key elements with significant consensus may indicate higherquality evidence or agreement on an accepted standard of care. For example, agreement was reached on the criteria for patient selection, which may reflect accepted transplantation criteria. 18 However, key elements with variability may represent areas of uncertainty. This uncertainty is evident in the key elements addressing anticoagulation and ventilation. Anticoagulation strategies show variation in drugs, dosing, and monitoring. Few programs addressed the management of coagulopathy associated with ECLS. This variability is seen internationally and may reflect uncertainty in the evidence related to anticoagulation on ECMO. [19][20][21] Similar uncertainty remains around ideal ventilatory practices for VV-and VA-ECMO. 12,22,23 This variation in practice may represent an opportunity for future research and qualityimprovement initiatives. It also highlights the need for outcome tracking in order to effectively implement such a program.
This study faced several limitations. The Delphi panel represented many of the institutions that shared documentation for the study, and the representative sample chosen may have led to sampling bias. This bias was minimized by ensuring representation from all provinces and also that at least 2 samples from each type of institution (lung and heart transplantation capable, heart transplantation capable, and cardiac surgery-only capable) were represented. Additionally, better characterization of the participating centres (eg, ECLS volume, academic vs community, geographic location) could have enriched the analysis and represents a limitation of this study. Also, it was impossible to verify that all program documentation was shared. Using ECLS leads or physicians with significant involvement in ECLS programs who would have the most familiarity with documentation should have mitigated this shortcoming. Finally, clinical practice may vary from what is described in program documentation.

Conclusion
Using an interdisciplinary panel, 37 key elements across 5 domains were identified that should be incorporated into ECLS protocols. Assessment of program documentation from Canadian institutions showed variability in the number of key elements included in protocols and how protocols addressed specific key elements. Further exploration of this variability could improve clinical care. The key-element framework   ANC, absolute neutrophil count; ARDS, acute respiratory distress syndrome; BMI, body mass index; CNS, central nervous system; CPR, cardiopulmonary resuscitation; ECMO, extracorporeal membrane oxygenation; FiO 2 , fraction of inspired oxygen; HIT, heparin-induced thrombocytopenia; NIV, noninvasive ventilation; PaO 2 , partial pressure of oxygen; pCO 2 , partial pressure of carbon dioxide; PEEP, positive endexpiratory pressure; P/F, PaO 2 /FiO 2 ; RESP score, respiratory ECMO survival prediction; SAPS, Simplified Acute Physiology Score; VV, veno-venous.   Provides parameters for monitoring post decannulation.

Process described only for VV-ECMO
Suggest consider weaning when patient shows signs of recovery such as pulsatility or recovery on ECHO No specific details about assessment for weaning CVP, central venous pressure; ECHO, echocardiogram; ECMO, extracorporeal membrane oxygenation; FiO 2 , fraction of inspired oxygen; LPM, liters per minute; LVEF, left ventricular ejection fraction; LVOT VTI, left ventricular outflow tract velocity time integral; MAP, mean arterial pressure; PA, pulmonary artery; PaO 2 , pulmonary artery partial pressure of oxygen; PEEP, positive end-expiratory pressure; PF, PaO 2 /FiO 2 ; Pplat, plateau pressure; SvO 2 ; venous oxygen saturation; VA, veno-arterial; VV, veno-venous. provides an opportunity for national collaboration on ECLS program development.